This invention relates to a method for treating disease using a camptothecin, and more specifically a method for treating disease using a camptothecin in combination with another drug.
20(S)-camptothecin, a plant alkaloid, was found to have anticancer activity in the late 1950""s. Wall, M. et al., Plant antitumor agents. I. The isolation and structure of camptothecin, a novel alkaloidal leukemia and tumor inhibitor from Camptotheca acuminata, J. Am. Chem. Soc. 88: 3888-3890, (1966); Monroe E. Wall et al., Camptothecin: Discovery to Clinic, 803 Annals of the New York Academy of Sciences 1 (1996). These documents, and all documents (articles, patents, etc.) cited to herein, are incorporated by reference into the specification as if reproduced fully below. The chemical formula of camptothecin was determined to be C20H16N2O4.
20(S)-camptothecin itself is insoluble in water. However, during the sixties and seventies the sodium salt of 20(S)-camptothecin was derived from 20(S)-camptothecin through opening of the lactone ring using a mild base. Clinical trials were then conducted using this hydrosoluble, sodium salt derivative of 20(S)-camptothecin (20(S)-camptothecin Na+), which was administered intravenously. The studies were later abandoned because of the high toxicity and low potency of 20(S)-camptothecin Na+. Gottlieb, J. A., et al., Preliminary pharmacological and clinical evaluation of camotothecin sodium salt (NSC 100880), Cancer Chemother. Rep. 54:461-470(1979); Muggia, F. M., et al., Phase I clinical trials of weekly and daily treatment with camptothecin (NSC 100880): Correlation with clinical studies, Cancer Chemother. Rep. 56:515-521 (1972); Gottlieb, J. A. et al., Treatment of malignant melanoma with camptothecin (NSC 100880), Cancer Chemother. Rep. 56:103-105 (1972); and Moertel, C. G., et al., Phase II study of camptothecin (NSC 100880) in the treatment of advanced gastrointestinal cancer, Cancer Chemother Rep. 56:95-101 (1972).
Despite its potential, interest in 20(S)-camptothecin as a therapeutic remained at a low ebb until the mid-1980""s. By that time, drug therapies were being evaluated for treating human cancer using human cancer xenograft lines. During these evaluations, human tumors are serially heterotransplanted into immunodeficient, so-called xe2x80x9cnudexe2x80x9d mice, and the mice then tested for their responsiveness to a specific drug. (Giovanella, B. C., et al., Cancer 52(7): 1146 (1983)). The data obtained in these studies strongly support the validity of heterotransplanted human tumors into immunodeficient mammals, such as nude mice, as a predictive model for testing the effectiveness of anticancer agents.
20(S)-camptothecin, and later some of its substituted forms, elicited differential responses in the cell cycle of nontumorigenic and tumorigenic human cells in vitro. Although it is not yet understood why 20(S)-camptothecin and some of its substituted forms are cytostatic for nontumorigenic cells and cytotoxic for tumorigenic cells, the selective toxicity of the compounds against tumorigenic cells in vitro and in vivo was an especially interesting feature of these drugs.
Investigators began to experiment with various substituted forms of 20(S)-camptothecin. Good activity was found when various substitutions were made to the 20(S)-camptothecin scaffold. For example, 9-Amino-20(S)-Camptothecin (9AC) and 10,11-Methylendioxy-20(S)-Camptothecin (10.11 MD) are capable of having high anticancer activity against human colon cancer xenografts. Giovanella, B. C., et al., Highly effective topoisomerase-l targeted chemotherapy of human colon cancer in xenocrafts, Science 246:1046-1048 (1989).
Additionally, 9-nitrocamptothecin (9 NC) has shown high activity against human tumor xenograft models. 9 NC has a nine position hydrogen substituted with a nitro moiety. 9 NC has inhibited the growth of human tumor xenografts in immunodeficient nude mice and has induced regression of human tumors established as xenografts in nude mice with little or no appearance of any measurable toxicity. D. Chatterjee et al., Induction of Apoptosis in Malignant and Camotothecin-resistant Human Cells, 803 Annals of the New York Academy of Sciences 143 (1996).
U.S. Pat. No. 5,552,154 to Giovanella et al. disclosed methods of treating specific forms of cancer with water-insoluble 20(S)-camptothecin and derivatives thereof, having the closed-lactone ring intact. In particular, transdermal, oral and intramuscular methods of administration using solutions of water-insoluble 20(S)-camptothecin were disclosed.
Other substituted 20(S)-camptothecin compounds that have shown promise include 7-ethyl-10-hydroxy 20(S)-camptothecin, and other 7, 9, 10, 11-substituted compounds.
A continuing need exists to develop new and improved ways to exploit the useful therapeutic activities of 20(S)-camptothecin and its various derivatives and analogs.
The present invention relates to new and improved compositions, kits, and methods for treating diseases using a combination therapy which includes 20(S)-camptothecin, an analog or 20(S)-camptothecin, or a derivative of 20(S)-camptothecin, collectively referred to herein as CPT. A therapeutic agent which exhibits a therapeutic synergistic effect with CPT is employed in the therapy.
A wide variety of non-CPT therapeutic agents with therapeutic synergistic effects with CPT may be employed. Examples of such nonCPT therapeutic agents include, but are not limited to alkylating agents, epidophyllotoxins, antimetabolites, antibiotics, and vinca alkaloids. Examples of alkylating agents include, but are not limited to cyclophosphamide, ifosfamide, melphalan, hexamethylmelamine, thiotepa and dacarbazine. Examples of antimetabolites include, but are not limited to 5-fluorouracil, cytarabine and folic acid analogs. Examples of folic acid analogs include, but are not limited to methotrexate, idatrexate or trimetrexate. Examples of antibiotics include, but are not limited to daunorubicine, doxorubicin, bleomycin or mitomycin. Examples of vinca alkaloids include, but are not limited to vinblastine, vincristine, and their synthetic analogues. Examples of epidophyllotoxin include, but are not limited to etoposide and teniposide.
The method may be used to treat a wide variety of diseases for which CPT has therapeutic activity. In one embodiment, the combination therapy methods and compositions of the present invention are useful in the treatment of neoplastic diseases.